Nociceptor Sensitization by Extracellular Signal-Regulated Kinases

Abstract

Inflammatory pain, characterized by a decrease in mechanical nociceptive threshold (hyperalgesia), arises through actions of inflammatory mediators, many of which sensitize primary afferent nociceptors via G-protein-coupled receptors. Two signaling pathways, one involving protein kinase A (PKA) and one involving the epsilon isozyme of protein kinase C (PKCepsilon), have been implicated in primary afferent nociceptor sensitization. Here we describe a third, independent pathway that involves activation of extracellular signal-regulated kinases (ERKs) 1 and 2. Epinephrine, which induces hyperalgesia by direct action at beta(2)-adrenergic receptors on primary afferent nociceptors, stimulated phosphorylation of ERK1/2 in cultured rat dorsal root ganglion cells. This was inhibited by a beta(2)-adrenergic receptor blocker and by an inhibitor of mitogen and extracellular signal-regulated kinase kinase (MEK), which phosphorylates and activates ERK1/2. Inhibitors of G(i/o)-proteins, Ras farnesyltransferases, and MEK decreased epinephrine-induced hyper-algesia. In a similar manner, phosphorylation of ERK1/2 was also decreased by these inhibitors. Local injection of dominant active MEK produced hyperalgesia that was unaffected by PKA or PKCepsilon inhibitors. Conversely, hyperalgesia produced by agents that activate PKA or PKCepsilon was unaffected by MEK inhibitors. We conclude that a Ras-MEK-ERK1/2 cascade acts independent of PKA or PKCepsilon as a novel signaling pathway for the production of inflammatory pain. This pathway may present a target for a new class of analgesic agents.

Catechol-O-methyltransferase inhibition alters pain and anxiety-related volitional behaviors through activation of β-adrenergic receptors in the rat

“…In the central nervous system, β 2 ARs are located on thalamic, cerebellar (Rainbow et al, 1984, Nicholas et al, 1996), and spinal dorsal horn neurons (Nicholson et al, 2005) as well as glial cells (Stone and Ariano, 1989, Salm and McCarthy, 1992). The contribution of β 2 ARs to enhanced pain sensitivity is in line with results from previous studies demonstrating that epinephrine activates β 2 ARs located on primary afferent nociceptors and produces a hyperalgesic state in rats (Khasar et al, 1999a, Khasar et al, 1999b, Aley et al, 2001, Khasar et al, 2003). Additionally, common variants of the human β 2 AR gene, coding for differences in receptor expression and internalization, are associated with the onset of TMD (Diatchenko et al, 2006).…”

Transient receptor potential A1 mediates gastric distention-induced visceral pain in rats

“…ERK1/2 activation in primary afferents has been suggested to be involved in peripheral sensitisation in acute pain conditions 25 26 27. We therefore examined the p-ERK1/2 labelling 2 min after mechanical stimulation (fig 6A).…”

MAPK activation in nociceptive neurons and pain hypersensitivity

“…Inflammatory mediators, such as prostaglandin E 2 , serotonin, epinephrine, and nerve growth factor (NGF), produce hyperalgesia through activation of protein kinase A (PKA) or protein kinase C (PKC) in primary afferent neurons (Gold et al, 1998;Khasar et al, 1999). Recently, it has been shown that the ERK cascade acts in epinephrine-induced hyperalgesia; also, the Ras-MEK-ERK pathway is activated independently of PKA or PKC (Aley et al, 2001;Dina et al, 2003). Furthermore, NGF injected into the peripheral tissue increases p-ERK labeling in tyrosine kinase A (trkA)-containing DRG neurons (Averill et al, 2001;Delcroix et al, 2003).…”